1. Field of the Invention
The present invention relates to a novel cephalosporin compound which is useful as an antibiotic agent. More particularly, the present invention relates to a cephem compound having (Z)-2-(2-aminothiazol(or aminothiadiazol)-4-yl)-2-(.alpha.-carboxy-3,4-substituted benzyloxyimino)acetamido group on 7.beta.-position and, at the same time, a 3-substituted propenyl group on C-3 position, that is, a cephalosporin compound represented by the following general formula (I), having an 4-amino-trisubstituted pyrimidinium substituent on 3-position of propenyl group: ##STR2## in which R.sup.1 represents hydrogen or an amino-protecting group,
R.sup.2 and R.sup.3 can be identical or different and independently of one another represent hydrogen or a hydroxy-protecting group, or PA1 R.sup.2 and R.sup.3 together can form a cyclic diol-protecting group, PA1 R.sup.4 represents hydrogen or a carboxyl-protecting group, PA1 R.sup.5, R.sup.6 and R.sup.7 independently of one another represent hydrogen, amino or substituted amino, hydroxy, alkoxy, C.sub.1-4 alkyl, carboxyl or alkoxycarbonyl, or PA1 R.sup.5 and R.sup.6 together with the carbon atoms to which they are attached can form a C.sub.3-7 cycle, and PA1 Q represents CH or N, PA1 R.sup.12 represents a monovalent etherified organic group which is linked with oxygen atom via carbon atom, PA1 B represents --S-- or &gt;S.fwdarw.O, and PA1 P represents an organic group. PA1 R.sup.14 represents C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, furylmethyl or thienylmethyl group, and PA1 R.sup.15 represents hydrogen, carbamoyl, carboxymethyl, sulfonyl or methyl group. PA1 R.sup.17 and R.sup.18 represent hydrogen, methyl, carboxyl, protected carboxyl or oxygen atom, PA1 R.sup.19 and R.sup.20 represent hydrogen or oxygen atom, PA1 R.sup.21 represents hydrogen or a carboxyl-protecting group, PA1 a, b and c are an integer of 0 or 1, and PA1 X represents hydrogen, hydroxyl or a group of formula ##STR6## PA1 R.sup.27 and R.sup.28 independently of one another represent hydroxy or substituted hydroxy, or R.sup.27 and R.sup.28 together can form a protected cyclic diol group, PA1 R.sup.29 and R.sup.30 represent hydrogen or a carboxyl-protecting group, PA1 R.sup.31 represents hydrogen or C.sub.1-3 alkyl group substituted with 1 to 3 halogen atom(s), PA1 Z represents &gt;S or &gt;S.fwdarw.O, and PA1 a dotted line denotes 2-cephem or 3-cephem compound. PA1 A represents a cyclic or acyclic ammonio group.
and its pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable ester, hydrate and solvate, and isomers thereof, which have a potent antimicrobial activity and a broad antibacterial spectrum.
The present invention also relates to a process for preparation of the compound of formula (I), as defined above, and to a pharmaceutical composition containing the compound of formula (I) as an active ingredient.
2. Background Art
Cephalosporin antibiotics have been widely used for treatment of diseases caused by pathogenic bacteria in human and animals and are particularly useful for treatment of diseases caused by bacteria which are resistant to other antibiotics such as penicillin compounds and for treatment of penicillin-hypersensitive patients. In most bacterial infections, it is preferable to use antibiotics which are active against both of gram-positive and gram-negative microorganisms. In addition, it has been well known that an antimicrobial activity of such cephalosporin antibiotics is greately influenced by the substituent on 3- or 7-position of the cephem nucleus. Accordingly, it has been attempted to develop an antibiotic compound which shows a high antibacterial activity against a broad range of gram-positive and gram-negative strains and is very stable to .beta.-lactamase produced by various gram-negative bacterial strains and is also very stable in the living body. As a result, heretofore, numerous cephalosporin antibiotics having various substituents on the 7.beta.-acylamido group and the 3-position of cephem nucleus have been developed.
For example, British Patent No. 1,399,086 broadly and generally describes a cephalosporin derivative represented by the following general formula (A): ##STR3## in which R.sup.11 represents hydrogen or an organic group,
Since the development of the above compounds it has been continuously attempted to develop an antibiotic compound having an improved antibacterial activity particularly against gram-negative strains. As a result of such attempts, British Patent No. 1,522,140 discloses a cephalosporin antibiotic compound represented by the folowing general formula (B), wherein the compound is present as a syn-isomer or a mixture of syn- and anti-isomers containing at least of 90% of syn-isomer: ##STR4## in which R.sup.13 represents furyl or thienyl group,
Subsequently, numerous studies have been made to develop an antibiotic compound having an improved antibacterial activity against gram-positive strains as well as against gram-negative strains and having a broad antibacterial spectrum. As a result thereof, numerous cephalosporin compounds having a structure similar to that of formula (B) above have been developed. Such development has induced various changes including the introduction of acylamido group into 7-position and a specific group into C-3 position in the cephem nucleus of formula (B).
For example, Belgian Patent No. 852,427 discloses a cephalosporin antibiotic compound which is derived from the compound of formula (A) by replacing R.sup.11 with various other organic groups such as 2-aminothiazol-4-yl group and attaching the oxygen atom of oxyamino group to an aliphatic hydrocarbon group which, in turn, can be substituted with carboxy group. In this compound, the substituent on C-3 position may be acyloxymethyl, hydroxymethyl, formyl, optionally substituted heterocyclic thiomethyl, and the like.
The compounds described in the above-mentioned patents are totally distinguished from the compounds of the present invention in their structures.
Recently, many efforts have been made to find out compounds having a potent antibacterial activity against a broad range of pathogenic organisms including some gram-negative bacterial strains which produce .beta.-lactamase. One attempt is to introduce a specific group, for example, various heterocyclic groups, aryl, or alkylsulfonylacyl, aryl or aralkyl groups, into C-7 position, particularly into R.sup.12 position in the compound of formula (A) wherein R.sup.11 is 2-aminothiazol-4-yl group. As a result, it has been identified that the cephem compounds wherein R.sup.12 is .alpha.-carboxy-3,4-substituted benzyl group show a potent antibacterial activity against broad range pathogenic organisms. Such cephem compounds have been disclosed in many patents such as PCT/JP86/00140, European Patent Application No. 87312525.2, etc.
Specifically, PCT/JP86/00140 discloses a cephem compound having the following general formula (C): ##STR5## in which R.sup.16 represents hydrogen or an amino-protecting group,
The specification of the above PCT application broadly describes the compounds so that the 7.beta.-position substituent may include (Z)-2-(2-aminothiazol-4-yl)-2-(.alpha.-carboxyl-3,4-substituted benzyloxyimino)acetamido group as described in the present invention. However, the structure of this compound is different from that of the compound of the present invention because in the moiety --CH.sub.2 Y present on C-3 position the hetero atom (S or N) of Y is bound to C-3 position of cephem nucleus via methylene bridge whereas in the compound of the present invention the hetero atom in the corresponding moiety is bound to the cephem nucleus via propenyl bridge. Furthermore, in the above patent application, although Y can represent some substituted pyridine groups, there is no mention or suggestion on the substituted pyrimidine group as described in the present invention.
In addition, European Patent Application No. 87308525.2 describes the cephem compound represented by the following general formula (D): ##STR7## in which R.sup.26 represents hydrogen or an amino-protecting group,
However, the substituent introduced into C-3 position in the above European patent is different from the C-3 substituent in the compound of the present invention.
Further, European Patent No. 264,091 discloses the cephem compounds haing the following general formula (E): ##STR8## in which R.sup.32 represents lower alkyl group substituted with fluoro, or lower alkyl group substituted with cyano group, and
The above patent discloses several cyclic ammonio groups as an example of A. However, there is no mention or suggestion on the pyrimidyl group as described in the present invention. Furthermore, the structure of 7-.beta. substituent in the compound of this patent is also different from that in the compound of the present invention.
On the basis of the above-mentioned prior art, the present inventors have extensively and continuously studied to develop a cephalosporin compound having a potent antibacterial activity against broad range of pathogenic microorganisms including .beta.-lactamase producing gram-negative bacteria strains and also having an improved pharmacokinetic property. As a result, we have identified that a certain cephalosporin compound having (Z)-2-(2-aminothiazol(or aminothiadiazol)-4-yl)-2-(.alpha.-carboxy-3,4-substituted benzyloxyimino)acetamido group on 7-.beta. position and, at the same time, an optionally substituted pyrimidinopropenyl group on C-3 position satifies the above-mentioned purpose. Thus, now we have completed the present invention.
Therefore, it is an object of the present invention to provide a novel cephalosporin compound having the general formula (I), as defined above, which has a potent antimicrobial activity, broad antibacterial spectrum and improved pharmacokinetic properties.
It is a further object of the present invention to provide a process for preparing the novel cephalosporin compound of formula (I).
Further, it is another object of the present invention to provide a pharmaceutical composition containing the novel cephalosporin compound of formula (I) as an active ingredient.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Other many beneficial results can be obtained by applying the disclosed invention in a different manner of modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention, in addition to the scope of the invention defined by the claims.